Scientific research on the diseases of the central nervous system has been of great interest in recent years, especially the diseases related to motor alterations. At present, the treatment of diseases related to motricity does not have genetic therapeutic approaches to diminish the symptoms.
One of the most characteristic motor neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). This progressive disease affects the motor nerve cells in the brain and the spinal cord which leads to paralysis and death. The misfolding and aggregation of the protein superoxide dismutase 1 (SOD1) is associated with the appearance of sporadic and familiar forms of ALS. Although the principal mechanism responsible for the progressive loss of the motor nerve cells in ALS continues being unknown, the latest evidence highlights the contribution of the alterations of the proteostasis or the protein equilibrium at the level of quantity and quality in the process of the disease. One of the events detected at an early pre-symptomatic stage of ALS in mouse models is the presence of stress response proteins in the endoplasmic reticulum (ER) of the secondary motor neurons.
The stress in the endoplasmic reticulum (ER) is buffered by the activation of the unfolded protein response (UPR), a homeostatic signaling network that orchestrates the recovery of the function of the organelle. On the other hand, the lack of adaptation to stress of the ER results in neuronal disfunction and apoptosis. UPR signaling relies upon regulation/activation of three principal transcription factors known as X-box binding protein 1 (XBP1), a factor that activates transcription 6 (ATF6) and transcription factor 4 (ATF4). Together, XBP1s, ATF6 and ATF4 allow the adaptation to stress, or in the case of ATF4 towards the elimination of cells that have been irreversibly damaged by apoptosis.
The pharmacological and genetic therapies that exist today are aimed mainly at the capacity of cellular adaptation, to reestablish the proteostasis of the endoplasmic reticule (ER) through gene expression of UPR. These studies have been carried out in preclinical models of neurodegenerative diseases with successful results.
Gene therapy using recombinant viruses is being used in our laboratory as an attractive strategy to deliver the components of the active UPR for specific areas of the brain. This method can also avoid the possible pleiotropic effects of the systemic and chronic administration of compounds with the objective of controlling ER stress. The adeno-associated viruses (AAV) are one of the options for the administration of therapeutic genes in the brain and the spinal cord due to their safety profile, as has been shown in clinical tests.
The research and development pipeline for treatment and/or prevention of ALS is broad ranging from small molecule compounds (e.g. derivation of 1,3-benzoathyazol, such as Riluzol) that can aid in delaying time to assisted ventilation by blocking of sodium channels sensitive to tetrodotoxin (Rilutek™) to genetic approaches like IGF-1 (Insulin growth factor-1) through the virus AAV4 (associated adenovirus serotype 4) made known in the document EP 2489733 A2; or the construct HIF11-alfa (inducible factor of hypoxia 1, subunit alfa) and a general adeno-associated virus made known in the document EP 2497500 A1, among others.
Part of this patent is the information contained, in its most varied range, in patent application CL 3590-2014. The previously mentioned patent application disclosed a XBP1s-containing AAV for the improvement of the memory, specifically in neuronal cells of the hippocampus, without being restrictive to only this specific sequence of XBP1. There are biological deposits of the plasmid pAAV-XBP1s-HA dated 5 Nov. 2014 in the international agency of biological deposits, American Type Culture Collection (ATCC), under deposit number PTA-121708.